Multiple myeloma (MM) is a disease of the hematological system in which plasma cells that have developed malignant characteristics engraft within the bone marrow (BM). There is a consensus that the microenvironment of the BM contains factors and conditions that play a major role in the myeloma survival and proliferation. The BM is known to be hypoxic (pO2~<32mmHg) and low pO2 is theoretically deleterious to the survival of MM and other cells, although myeloma cells have developed adaptive responses that favor their survival and spread in this harsh microenvironment. Chief among these responses is the induction of master genes by hypoxia inducible factors (HIFs) that regulate various pathways protecting MM cells from hypoxia- mediated apoptosis. Many MM tumors exhibit constitutive HIF expression as a result of oncogene activation and/or genetic mutations in the O2-sensing/HIF pathway and we hypothesize that this likely contributes to a more malignant tumor phenotype and facilitates the progression of the disease. Thus, we believe that inhibiting HIF activity and overcoming these adaptive hypoxic responses may have major clinical significance in treating this disease. Indeed, we have shown that targeting HIF activity with a polyamide compound (HIF- PA) that blocks the ability of HIF to bind to its cognate DNA sequence sensitizes MM to hypoxia-mediated killing in vitro and has anti-tumor efficacy against MM xenografts in vivo. The focus of this MERIT is to examine the role of HIF transcription factors in survival and growth of MM cells and its impact on acid/base regulation and the formation of osteolytic bone lesions. To this end, we will examine the responses of established MM cell lines and patient derived tumor cells from myeloma of patients with different severity of diseases. To complement these in vitro studies, we will utilize novel orthotopic xenograft models to study how hypoxia regulates the MM/BM microenvironment and determine the pre-clinical efficacy of targeting HIF in vivo.